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An evolutionarily conserved DNA architecture determines target specificity of the TWIST family bHLH transcription factors.
Chang, Andrew T; Liu, Yuanjie; Ayyanathan, Kasirajan; Benner, Chris; Jiang, Yike; Prokop, Jeremy W; Paz, Helicia; Wang, Dong; Li, Hai-Ri; Fu, Xiang-Dong; Rauscher, Frank J; Yang, Jing.
  • Chang AT; Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093, USA; The Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, California, 92093, USA;
  • Liu Y; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
  • Ayyanathan K; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
  • Benner C; Salk Institute for Biological Studies, La Jolla, California 92037, USA;
  • Jiang Y; Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093, USA; The Biological Science Graduate Program, University of California at San Diego, La Jolla, California, 92093, USA;
  • Prokop JW; Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA;
  • Paz H; Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093, USA;
  • Wang D; Department of Cell and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USA;
  • Li HR; Department of Cell and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USA;
  • Fu XD; Department of Cell and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USA;
  • Rauscher FJ; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA; jingyang@ucsd.edu rauscher@wistar.org.
  • Yang J; Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093, USA; Department of Pediatrics, University of California at San Diego, La Jolla, California, 92093, USA jingyang@ucsd.edu rauscher@wistar.org.
Genes Dev ; 29(6): 603-16, 2015 Mar 15.
Article en En | MEDLINE | ID: mdl-25762439
ABSTRACT
Basic helix-loop-helix (bHLH) transcription factors recognize the canonical E-box (CANNTG) to regulate gene transcription; however, given the prevalence of E-boxes in a genome, it has been puzzling how individual bHLH proteins selectively recognize E-box sequences on their targets. TWIST is a bHLH transcription factor that promotes epithelial-mesenchymal transition (EMT) during development and tumor metastasis. High-resolution mapping of TWIST occupancy in human and Drosophila genomes reveals that TWIST, but not other bHLH proteins, recognizes a unique double E-box motif with two E-boxes spaced preferentially by 5 nucleotides. Using molecular modeling and binding kinetic analyses, we found that the strict spatial configuration in the double E-box motif aligns two TWIST-E47 dimers on the same face of DNA, thus providing a high-affinity site for a highly stable intramolecular tetramer. Biochemical analyses showed that the WR domain of TWIST dimerizes to mediate tetramer formation, which is functionally required for TWIST-induced EMT. These results uncover a novel mechanism for a bHLH transcription factor to recognize a unique spatial configuration of E-boxes to achieve target specificity. The WR-WR domain interaction uncovered here sets an example of target gene specificity of a bHLH protein being controlled allosterically by a domain outside of the bHLH region.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Modelos Moleculares / Proteínas de Drosophila / Proteína 1 Relacionada con Twist Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Año: 2015 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Modelos Moleculares / Proteínas de Drosophila / Proteína 1 Relacionada con Twist Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Año: 2015 Tipo del documento: Article